The long term objective of this proposal is to study the role of various factors in the pathogenesis of oral vesiculo-bullous diseases. Pemphigus was chosen as a model because it is one of the few oral diseases that is potentially fatal. Our hypothesis states that MHC genes are involved in its susceptibility to oral pemphigus and is in the production of anti-intercellular (ICS) or pemphigus antibody. Furthermore, different MHC class II gene products from different individuals recognize different immunodominant portions of the pemphigus antigen. In our preliminary studies, we have -studied, by HLA typing and restriction fragment length polymorphisms (RFLP), 51 pemphigus patients and their families. Our data indicate that the majority of the Jewish patients have [HLA-B38 DR4 SC3] DQw8] or B35 SC31 DR4 DQw8 extended haplotypes and non-Jewish patients have B35, DR4, SC31, DQw8 and a rare [HLA-Bw55 DRwl4 SB45 DQw5] extended haplotypes. Using an immunofluorescence and an immunoblot assay, sera of family members of patients have anti-ICS antibody. It is proposed that sequencing of the HLA - DQ DR regions of patients haplo-identical and matched normal controls be done to determine if there are unique "disease-specific" haplotypes to define a true "susceptibility gene". Comparison of sequences between patients, antibody producing and non-producing relatives and MHC matched control will help focus on a specific gene for anti-ICS antibody production. Using a variety of immunochemical techniques various immunodominant portions of the pemphigus molecule will be identified. It is expected that different MHC Class 11 gene products (DR4 and DRwl4) will identify different portions of the molecules. This work is possible because 51 patients and their family members and 100 ethnically and MHC matched controls have been characterized by RFLP. Dr. Ahmed is a dermatologist with additional training (Doctor of Medical Sciences, HSDM) in oral biology and oral pathology and an interest in blistering diseases. He has the support and cooperation of two senior immunogeneticists, Dr. Alper and Dr. Yunis who in addition to providing academic guidance and comments will also i actively participate in the project. The Center for Blood Research has a panel of over 3000 individuals who have been genotyped and provide a large reservoir of control data for such research. The information obtained from studying the molecular pathogenesis of oral pemphigus can be the framework for studying other blistering diseases like oral pemphigoid, erythema multiforme, toxic epidermal necrolysis and others.